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Antiretroviral Treatment of HIV Infection


Edward R. Cachay

, MD, MAS, University of California, San Diego School of Medicine

Reviewed/Revised Feb 2023
Topic Resources

Because disease-related complications can occur in untreated patients with high CD4 counts and because less toxic drugs have been developed, treatment with antiretroviral therapy (ART) is now recommended for all patients. The benefits of ART outweigh the risks in every patient group and setting that has been carefully studied.

ART aims to

  • Reduce the plasma HIV RNA level to undetectable (ie, < 20 to 50 copies/mL)

  • Restore the CD4 count to a normal level (immune restoration or reconstitution)

ART can usually achieve its goals if patients take their drugs > 95% of the time.

If treatment fails, drug susceptibility (resistance) assays can determine the susceptibility of the dominant HIV strain to all available drugs. Genotype assays may also be helpful.

Many patients living with HIV infection are taking complex regimens involving multiple pills. With the availability of new co-formulated HIV drugs, many patients could benefit from simplification of their ART regimen, guided by HIV DNA archive genotype testing (GenoSure Archive).

Classes of antiretrovirals

Multiple classes of antiretrovirals are used in ART. Two classes inhibit HIV entry, and the others inhibit one of the 3 HIV enzymes needed to replicate inside human cells; 3 classes inhibit reverse transcriptase by blocking its RNA-dependent and DNA-dependent DNA polymerase activity.

  • Nucleoside reverse transcriptase inhibitors (NRTIs) are phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and terminate synthesis of DNA chains.

  • Nucleotide reverse transcriptase inhibitors (nRTIs) competitively inhibit the HIV reverse transcriptase enzyme, as do NRTIs, but do not require initial phosphorylation.

  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind directly to the reverse transcriptase enzyme.

  • Protease inhibitors (PIs) inhibit the viral protease enzyme that is crucial to maturation of immature HIV virions after they bud from host cells.

  • Entry inhibitors (EIs), sometimes called fusion inhibitors, interfere with the binding of HIV to CD4+ receptors and chemokine co-receptors; this binding is required for HIV to enter cells. For example, CCR-5 inhibitors block the CCR-5 receptor.

  • Post-attachment inhibitors bind to the CD4 receptor and prevent HIV (that also binds to the CD4 receptor) from entering the cell.

  • Integrase inhibitors prevent HIV DNA from being integrated into human DNA.

  • Attachment inhibitors bind directly to the viral envelope glycoprotein 120 (gp120), close to the CD4+ binding site, which prohibits the conformational change necessary for initial interaction between the virus and the surface receptors on CD4 cells, thereby preventing attachment and subsequent entry into host T cells and other immune cells.

Antiretroviral regimens

Combinations of 2, 3, or 4 drugs from different classes are usually necessary to fully suppress replication of wild-type HIV. The specific drugs are chosen based on the following:

  • Anticipated adverse effects

  • Simplicity of regimen

  • Concomitant conditions (eg, hepatic or renal dysfunction)

  • Other drugs being taken (to avoid drug interactions)

To maximize adherence, clinicians should choose an affordable, well-tolerated regimen that uses once/day (preferable) or twice-a-day dosing. Guidelines from expert panels for initiating, selecting, switching, and interrupting therapy and special issues concerning treatment of women and children change regularly and are updated on the U.S. Department of Health and Human Services website, AIDSinfo.

Tablets containing fixed combinations of ≥ 2 drugs are now widely used to simplify regimens and improve adherence.

Tablets containing fixed combinations of one drug with cobicistat, which is a pharmacokinetic enhancer devoid of anti-HIV activity to increase the amount of medicine with HIV activity in the blood, can be used.

Adverse effects with combination tablets are the same as those for the individual drugs included.

Intramuscular injectable long-acting medications

This regimen consists of 2 antiretrovirals with a long-acting suspension formulation: rilpivirine, an NNRTI (non-nucleoside reverse transcriptase inhibitor), and the integrase inhibitor cabotegravir. The regimen can be administered as an intramuscular injection every 2 months. Patients who wish to consider this injectable regimen must be adults infected with HIV who are on a stable regimen and who are virologically suppressed (HIV-1 viral load < 50 copies per milliliter) with no history of treatment failure and with no known or suspected resistance to either rilpivirine or cabotegravir. Patients with active hepatitis B infection Hepatitis B, Acute Hepatitis B is caused by a DNA virus that is often parenterally transmitted. It causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice. Fulminant hepatitis and... read more are often excluded, because this regimen does not have treatment spectrum against hepatitis B. Patients often start their treatment with oral cabotegravir and rilpivirine for 4 weeks to assess how well they tolerate the drug. Common adverse effects are injection site pain, low-grade fever, and headaches. Hypersensitivity post-injection reactions are rare. This long-acting injectable regimen is still of limited use in most parts of the world with the highest HIV burden.

Drug interactions

Interactions between antiretrovirals may increase or decrease efficacy.

For example, efficacy can be increased by combining a subtherapeutic dose of ritonavir (100 mg once/day) with another protease inhibitor (PI) (eg, darunavir, atazanavir). Ritonavir inhibits the hepatic enzyme that metabolizes the other PI. By slowing clearance of the therapeutically dosed PI, ritonavir increases the other drug’s levels, maintains the increased levels longer, decreases the dosing interval, and increases efficacy. Another example is lamivudine (3TC) plus zidovudine (ZDV). Use of either drug as monotherapy quickly results in resistance, but the mutation that produces resistance in response to 3TC increases the susceptibility of HIV to ZDV. Thus, when used together, they are synergistic.

Conversely, interactions between antiretrovirals may decrease the efficacy of each drug. But, these combinations are rarely used in clinical practice anymore (eg, ZDV and stavudine [d4T]).

Combining drugs often increases the risk that either drug will have an adverse effect. Possible mechanisms include the following:

  • Hepatic metabolism of PIs by cytochrome P-450: The result is decreased metabolism (and increased levels) of other drugs.

  • Additive toxicities: For example, combining first-generation NRTIs, such as stavudine (d4T) and didanosine (ddI), increases the chance of adverse metabolic effects and peripheral neuropathy. Also, using a tenofovir disoproxil fumarate in a ritonavir-boosted regimen increases the plasma levels of tenofovir disoproxil and, in susceptible patients with certain comorbidities, causes renal dysfunction.

Many drugs may interfere with antiretrovirals. Coformulated bictegravir is contraindicated when coadministering with a tuberculosis treatment containing rifampin or rifabutin. The levels of bictegravir fall too much due to the presence of inducer effect of rifampin/rifabutin and predispose to the risk of HIV viral failure (see Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents: Drug-Drug Interactions); thus, interactions should always be checked before any new drug is started.

In addition to drug interactions, the following influence activity of some antiretroviral drugs and should be avoided:

Adverse effects of antiretrovirals

Antiretrovirals can have serious adverse effects. Some of these effects, notably anemia, hepatitis, renal insufficiency, pancreatitis, and glucose intolerance, can be detected by blood tests before they cause symptoms. Patients should be screened regularly, both clinically and with appropriate laboratory testing (complete blood count; blood tests for hyperglycemia, hyperlidemia, hepatic and pancreatic damage, and renal function; urinalysis), especially after new drugs are started or unexplained symptoms develop.

Metabolic effects consist of interrelated syndromes of fat redistribution, hyperlipidemia, and insulin resistance. Subcutaneous fat is commonly redistributed from the face and extremities to the trunk, neck, breasts, and abdomen—a cosmetic effect that can stigmatize and distress patients called lipodystrophy. Treating the resulting deep facial grooves with injected collagen or polylactic acid can be beneficial.

Antivirals from all classes appear to contribute to these metabolic effects, but PIs are the most clearly involved. Some older ART drugs, such as ritonavir or d4T, commonly have metabolic effects. Others, such as tenofovir disoproxil fumarate, etravirine, atazanavir or darunavir (even when combined with low-dose ritonavir), raltegravir, and maraviroc, appear to have small to minimal effects on lipid levels.

Mechanisms for metabolic effects appear to be multiple; one is mitochondrial toxicity. Risk of metabolic effects (highest with PIs) and mitochondrial toxicity (highest with NRTIs) varies by drug class and within drug classes (eg, among NRTIs, highest with d4T).

Metabolic effects are dose-dependent and often begin in the first 1 to 2 years of treatment. Lactic acidosis is uncommon but can be lethal.

Nonalcoholic fatty liver disease Metabolic Dysfunction–Associated Liver Disease (MASLD) Steatotic liver disease is due to excessive accumulation of lipid in hepatocytes. Metabolic dysfunction–associated liver disease (MASLD) includes simple fatty infiltration (a benign condition... read more is being increasingly recognized among patients living with HIV. Certain early-generation ART drugs caused steatosis, and as their use decreased, incidence of steatosis decreased. Nonetheless, even with newer-generation ART drugs, there appears to be a risk of steatosis.

Long-term effects and optimal management of metabolic effects are unclear. Lipid-lowering drugs (statins) and insulin-sensitizing drugs (glitazones) may help. Patients should be counseled about maintaining a healthy diet and regular physical activity as ways to help promote health. (See also the recommendations of the HIV Medicine Association of the Infectious Diseases Society of America and the Adult AIDS Clinical Trials Group: Guidelines for the evaluation and management of dyslipidemia in HIV-infected adults receiving antiretroviral therapy.)

Bone complications of ART include asymptomatic osteopenia and osteoporosis, which are common. Uncommonly, osteonecrosis of large joints such as the hip and shoulder causes severe joint pain and dysfunction. Mechanisms of bone complications are poorly understood.

Lipodystrophy (Lipoatrophy) in HIV

Immune reconstitution inflammatory syndrome (IRIS)

Patients beginning ART sometimes deteriorate clinically, even though HIV levels in their blood are suppressed and their CD4 count increases, because of an immune reaction to subclinical opportunistic infections or to residual microbial antigens after successful treatment of opportunistic infections (see immune reconstitution inflammatory syndrome Immune reconstitution inflammatory syndrome (IRIS) Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more Immune reconstitution inflammatory syndrome (IRIS) for a more detailed discussion).

Interruption of antiretroviral therapy

Interruption of ART is usually safe if all drugs are stopped simultaneously, but levels of slowly metabolized drugs (eg, nevirapine) may remain high and thus increase the risk of resistance. Interruption may be necessary if intervening illnesses require treatment or if drug toxicity is intolerable or needs to be evaluated. After interruption to determine which drug is responsible for toxicity, clinicians can safely restart most drugs as monotherapy for up to a few days.

Pearls & Pitfalls

  • Patients who had an adverse reaction to abacavir should not be given the drug again. If they are reexposed to the drug, they may have a severe, potentially fatal hypersensitivity reaction. Risk of an adverse reaction to abacavir is 100-fold higher in patients with HLA-B*57:01, which can be detected by genetic testing.

NOTE: The most important exception is abacavir; patients who had fever or rash during previous exposure to abacavir may develop severe, potentially fatal hypersensitivity reactions with reexposure. Risk of an adverse reaction to abacavir is 100-fold higher in patients with HLA-B*57:01, which can be detected by genetic testing.

More Information

The following English-language resources may be useful. Please note that The Manual is not responsible for the content of these resources.

Drugs Mentioned In This Article

Drug Name Select Trade
Apretude, VOCABRIA
Epivir, Epivir HBV
Zerit, Zerit Powder, Zerit XR
Videx, Videx EC, Videx Pediatric
Rifadin, Rifadin IV, Rimactane
Fortovase, Invirase
No brand name available
Isentress, Isentress HD
Viramune, Viramune Suspension, Viramune XR
Ziagen, Ziagen Solution
NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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